Similar to peptides, oligonucleotides, and oligosaccharides, most small molecule natural products are modular in their constitution. Like the aforementioned oligomers, the majority of naturally occurring small molecules are biosynthesized via the sequential coupling of bifunctional building blocks. Specifically, polyketides are derived from multiple malonyl-CoA and/or methylmalonyl-CoA units, non-ribosomal peptides are built from amino acids, polyterpenes are stitched together from isopentenyl pyrophosphate and/or dimethylallyl pyrophosphate building blocks, and fatty acids are prepared from fragments of malonyl-CoA. Other classes of modular natural products result from the oxidative coupling of common building blocks, such as shikimic acid, amino acids, and/or their respective derivatives.
With peptides and oligonucleotides, and increasingly with oligosaccharides, the inherent modularity is now routinely harnessed to enable fully automated syntheses from suitably protected bifunctional building blocks (R. B. Merrifield, Science 1965, 150, 178-185; M. H. Caruthers, Science 1985, 24, 799; and O. J. Plante, M. R. Palmacci, P. H. Seeberger, Science 2001, 291, 1523). As a direct result of these advances, research in these areas is primarily focused on discovering and understanding new molecular function. In stark contrast, despite tremendous advances over the course of nearly two centuries, the laboratory synthesis of small molecules remains a relatively complex, inflexible, and non-systematized process practiced almost exclusively by highly-trained specialists. (For pioneering developments in the automated synthesis of small molecules via polymer-assistance and/or flow chemistry, see: a) C. H. Hornung, M. R. Mackley, I. R. Baxendale, and S. V. Ley, Org. Proc. Res. Dev. 2007, 11, 399-405; b) Nikzad Nikbin, Mark Ladlow, and Steven V. Ley, Org. Process Res. Dev. 2007, 11, 458-462; and c) S. France, D. Bernstein, A. Weatherwax, and T. Lectka, Org. Lett. 2005, 7, 3009-3012.) Thus, research in this area is still heavily weighted towards synthesis. Given the special properties of many small molecules that make them uniquely suited for a wide range of applications in science, engineering, and medicine, increased access to these compounds via a highly general and automated synthesis platform that is accessible to the non-expert would be highly enabling. Ultimately, such a process could help shift the primary focus from the synthesis of small molecules to the discovery and understanding of important small molecule functions.
Organoboron compounds have had a profound impact on organic synthesis. Their unique reactivity has made them among the most versatile organometallic intermediates (boronate building blocks) for the construction of complex organic molecules.
The Suzuki-Miyaura reaction is a palladium- or nickel-catalyzed cross-coupling between a boronic acid or a boronic ester and an organohalide or an organo-pseudohalide. Miyaura et al. (1995) Chem Rev 95:2457-83. This cross coupling transformation is a powerful method for C—C bond formation in complex molecule synthesis. The reaction is tolerant of functional groups and has become increasingly general and widespread in its use for coupling of organic compounds. Barder et al. (2005) J Am Chem Soc 127:4685-96; Billingsley et al. (2007) J Am Chem Soc 129:3358-66; Littke et al. (2000) J Am Chem Soc 122:4020-8; Nicolaou et al. (2005) Angew Chem Int Ed 44:4442-89.
Boronic acids, on the other hand, are notoriously sensitive to many common reagents. Hall D G, Boronic Acids, Wiley-VCH, Germany, 2005, pp 3-14; Tyrell et al. (2003) Synthesis 4:469-83. It is therefore typical to introduce the boronic acid functional group during the last step of a building block synthesis. However, many of the methods for doing so (hydroboration, trapping organometallic reagents with trimethylborate, etc.) are intolerant to a variety of common functional groups, such as alcohols, aldehydes, ketones, alkynes and olefins. This makes the synthesis of structurally complex boronic acid building blocks quite challenging.
Conventional boronic acids are characterized by sp2-hybridized boron covalently linked to a carbon atom of an organic moiety of interest. Incompatibility of most oxidants with these boronic acids represent a significant limitation because it severely restricts the ability to modify the organic moiety while retaining the carbon-boron bond.
Recently there has been keen interest in the development of protecting groups for the boronic acid functional group. A compound that includes a protected boronic acid and another functional group can undergo chemical transformations of the other functional group without chemically transforming the boron. Removal of the protecting group (deprotection) then provides the free boronic acid, which can undergo a Suzuki-Miyaura reaction to cross-couple the compound with an organohalide or an organo-pseudohalide.
Toward this end, Molander and Ribagorda described potassium organotrifluoroborates useful in Suzuki-Miyaura cross-coupling reactions and epoxidation reactions. Molander et al. (2003) J Am Chem Soc 125:11148-9.
More recently, N-methyliminodiacetic acid (MIDA) “rigid cage” boronates have been described as a highly versatile platform for synthesizing boronate building blocks. US 2009/0030238 (incorporated herein by reference). These MIDA boronates are characterized by the presence of boron having sp3 hybridization covalently linked to a carbon atom of an organic moiety of interest, wherein the boron is remarkably stable in the face of harsh chemical conditions capable of transforming the functional group, yet deprotection is effectively achieved using mild aqueous basic conditions (e.g., treatment with 1 M aqueous sodium hydroxide in tetrahydrofuran for 10 minutes). Dozens of MIDA boronates are now commercially available from Aldrich.
Many biologically active compounds and pharmaceuticals are synthesized as racemic mixtures, while most, if not all, of the desired biological activity is typically associated with only one enantiomer of such compounds. It is, therefore, not surprising that there is tremendous interest in being able to synthesize organic molecules with directed stereochemistry, including, for example, for high throughput screening for biologically relevant activity.
A building-block approach to small molecule synthesis is an attractive strategy for constructing specific complex molecules as well as for generating libraries of compounds. In an idealized form of the building-block approach to small molecule synthesis, off-the-shelf subunits having all the required functional groups pre-installed in the correct oxidation states and with the desired stereochemical relationships are brought together using a single reaction iteratively.